Mitigation of cardiovascular toxicity in a series of CSF-1R inhibitors, and the identification of AZD7507

Scott, David A.; Dakin, Les A.; Daly, Kevin; Valle, David J. Del; Diebold, R. Bruce; Drew, Lisa; Jayachandran, Ezhuthachan; Gero, Thomas W.; Ogoe, Claude A.; Omer, Charles A.; Redmond, Sean; Repik, Galina; Thakur, Kumar; Ye, Qing; Zheng, Xiaolan

doi:10.1016/j.bmcl.2013.06.031

Cited by 23 publications

(20 citation statements)

References 17 publications

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“…Compounds were dissolved into PBS (Gibco) and added to media to treat cells. AZD7507 CSF1R has been previously described (Scott et al, 2013). FCCP, oligomycin, rotenone, antimycin A were from Sigma-Aldrich and stocks were prepared in DMSO; etomoxir, carnitine, palmitate, were from Sigma-Aldrich and prepared in water, BSA fraction V was from Roche and prepared in water.…”

Section: Methodsmentioning

confidence: 99%

Macrophage Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

Halbrook

Pontious

Lee

et al. 2018

Preprint

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Pancreatic Ductal Adenocarcinoma (PDA) is characterized by abundant infiltration of tumor associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, the front-line chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism.Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Additionally, we report pyrimidine release is a general function of anti-inflammatory myeloid cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.

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Section: Methodsmentioning

confidence: 99%

Macrophage Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

Halbrook

Pontious

Lee

et al. 2018

Preprint

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“…Scott and co-workers (AstraZeneca) generated intermediate 87 in the synthesis of oncology target 88 by reacting ortho-substituted aryl bromide 86 and piperazine ( Scheme 14 a). 94 The reaction occurred in the presence of an L6 -based catalyst and at high temperature using a polar aprotic solvent (dimethylacetamide). Park and co-workers (SK Chemicals) were able to selectively functionalize unprotected piperazine 90 at the less-hindered nitrogen of the nucleophile ( Scheme 14 b).…”

Section: Alkylaminesmentioning

confidence: 99%

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

2016

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Pd-catalyzed cross-coupling reactions that form C–N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C–N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.

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“…Within 21 days all mice had palpable tumors at the injection site. Xenografted mice were given liposomal clodronate (Lipclod) to selectively deplete phagocytic macrophages; GW2580 or AZD7507 ( Figure 5A) to inhibit the activation of CSF receptor 1 (CSFR1), thereby preventing monocyte differentiation into macrophages; or appropriate vehicle alone (41)(42)(43)(44). Tumors were isolated 8 hours after the final dose of each compound.…”

Section: Loss Of Macrophage-derived Wnt Inhibits CC Growth In Vivomentioning

confidence: 99%

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

Boulter¹,

Guest²,

Kendall³

et al. 2015

J. Clin. Invest.

233

242

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Mitigation of cardiovascular toxicity in a series of CSF-1R inhibitors, and the identification of AZD7507

Cited by 23 publications

References 17 publications

Macrophage Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

Macrophage Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

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